CN1118308C - Device for electrodermal delivery of fentanyl and sufentanil - Google Patents

Abstract

The present invention provides an improved electrotransport system for the delivery of analgesic drugs, namely fentanyl and sufentanil. The fentanyl/sufentanil is provided as a water-soluble halide salt (e.g., fentanyl hydrochloride), preferably contained in a hydrogel formulation, for use with an electrotransport device (10). In accordance with the present invention, the donor electrode (22) of the electrotransport device (10) is comprised of silver, and the donor reservoir (26) is substantially free of supplemental chloride ion sources and contains a predetermined "excess" loading of fentanyl/sufentanil for preventing silver ion migration to cause skin discoloration.

Description

Device for electrodermal delivery of fentanyl and sufentanil

The present invention relates generally to devices, compositions, and methods for improved electrodelivery of analgesic drugs, particularly fentanyl and fentanyl analogs.

Transdermal drug delivery by diffusion through the epidermis has many advantages over traditional methods such as subcutaneous injection or oral administration. Delivering drugs through the skin avoids the first pass through the liver of oral drugs. Transdermal drug delivery also eliminates patient pain associated with subcutaneous injections. In addition, transdermal drug delivery may provide more uniform drug concentrations in the patient's bloodstream due to the extended controlled delivery profile of some types of transdermal delivery devices. The term "transdermal" delivery broadly includes the delivery of an agent through a body surface such as the skin, mucous membranes, or nails of an animal.

The function of the skin is primarily to act as a barrier to the entry of substances into the body through the skin and to be the primary barrier to transdermal delivery of therapeutic agents such as drugs. Efforts to date have focused on reducing physical resistance or enhancing skin permeability for drug delivery through passive diffusion. A number of approaches have been attempted to increase drug flux through the skin, the most notable being the use of chemical flux enhancers.

Other methods of increasing the flow rate of transdermal drug delivery include the use of additional energy sources, such as electrical energy and ultrasonic energy. Electro-assisted transdermal delivery is also known as electrotransport. As used herein, the term "electrotransport" generally refers to the delivery of an agent (eg, a drug) through a surface such as the skin, a mucosal surface, or a nail. Transport is induced or facilitated by the application of an electrical potential. For example, beneficial therapeutic agents can be introduced into the systemic circulation of the body by means of transdermal electrotransport. One widely used method of electrotransport is the electrotransport method (also known as iontophoresis) involving the electrically induced transport of charged ions. Another method of electrotransport is electroosmosis, which involves the flow of a liquid containing the agent to be delivered under the influence of an electric field. Yet another method of electrotransport is electrotransport, which involves the formation of transient pores within the surface layer of an organism by means of the application of an electric field. Agents can be delivered through the pores either passively (ie without the aid of electricity) or actively (ie under the action of an electrical potential). However, in any known method of electrotransport there is involved at least some "passive" diffusion which may occur to some degree concurrently. Incidentally, the term "electrotransport" as used herein should be given the broadest interpretation such that it includes the electrically induced or enhanced transport of at least one agent, which may be charged, uncharged or mixed, and any The specific mechanism used to deliver the agent.

Electrotransport devices use at least two electrodes that are in electrical contact with a location on the skin, nails, mucosal surface, or other body surface. One of these electrodes, often called the "donor" electrode, is where the drug is delivered to the body. The other electrode, generally called the "opposite" electrode, is used to complete a closed circuit through the body. For example, if the agent to be delivered into the body is positively charged, ie, a cation, the anode is the donor electrode and the negative electrode (cathode) is the opposite electrode, used to form the electrical circuit. If the agent to be delivered is negatively charged, ie an anion, then the cathode is the donor electrode and the anode is the opposite electrode. Incidentally, both the anode and cathode can be considered donor electrodes if cationic and anionic agent ions are delivered or if uncharged dissolved agents are delivered.

Furthermore, electrotransport systems typically require at least one container or source of an agent to be delivered to the body. Examples of such donor containers include cassettes or chambers, porous sponges or pads, and hydrophilic polymer or gel matrices. Such a donor container is electrically connected and fixed between the anode or cathode and the surface of the body for providing a fixed or renewable source of one or several drugs or agents. The electrotransport device also has a power source, such as one or more batteries. Typically at any one time, one pole of the power source is electrically connected to the donor vessel, while the opposite pole is connected to the opposite electrode. Since the flow rate of electrodelivered drugs has been shown to be approximately proportional to the current supplied by the device, many electrotransport devices have electrical controllers for controlling the voltage and/or current applied through the electrodes to adjust the drug delivery flow rate. These control circuits use various electrical components for controlling the magnitude, polarity, timing, waveform, etc. of the voltage and/or current applied by the power supply. See, eg, US Patent 5,047,007 to McNichols et al.

Transdermal electrodermal drug delivery devices currently on the market (such as the Phoresor sold by Lomed Corporation of Salt Lake City, UT; the Dupel Iontophoresis system sold by Empi Corporation of St. Paul, MN; the Dupel Iontophoresis system sold by Wescor Corporation of Logan, UT The WebsterSweat Inducer, Model 3600) generally utilizes a benchtop power supply unit and a pair of skin contact electrodes. The donor electrode contains a drug solution and the counter electrode contains a biocompatible electrolytic salt solution. The power supply unit has an electrical control unit for adjusting the amount of current applied through the electrodes. The "satellite" electrodes are connected to the power supply unit by long (eg 1-2 meter) wires or cables. The connections of the wires are prone to disconnection and limit the patient's movement and dexterity. The wires between the electrodes and the control unit are inconvenient or uncomfortable for the patient. Other examples of desktop power supply units using "satellite" electrode assemblies are disclosed in US Patent 4,141,359 to Jacobsen et al. .

A small, self-contained electrotransport device that is worn on the skin for extended periods of time, sometimes inconspicuously under clothing, has recently been proposed. For example, such small self-contained electrotransport devices are disclosed in Tapper, US Patent 5,224,927, Sibalis et al., US Patent 5,224,928, and Haynes et al., US Patent 5,246,418. WO 93/01807 describes a self-contained transdermal drug delivery system with an active drug container that delivers drug by iontophoresis and a passive drug container that delivers drug by diffusion. In one example, a system for transdermal delivery of fentanyl is provided, and in another example, a system for transdermal delivery of sufentanyl is provided. This document also describes a number of passive and iontophoretic transdermal drug delivery systems.

The use of electrotransport devices with reusable controllers adapted to use with a variety of medicated devices has recently been proposed. The medicated device is simply detached from the controller when the drug is used up, and a new medicated device is then attached to the controller. In this way, the relatively expensive hardware components of the device (e.g. batteries, LEDs, circuit hardware, etc.) can be housed in a reusable controller, while the inexpensive donor container and conversely container base can be housed in a disposable In the drug-containing device, thereby reducing the cost of the entire electrotransport device. Examples of electrotransport devices that include reusable controllers that are detachable from the drug-containing device are in Sage, Jr. et al. US Patent 5,320,597 and Sibalis US Patent 5,358,483, Sibalis et al. ), disclosed in UK patent application 2 239 803 by Devane et al.

In other developments of electrotransport devices, the use of hydrogels as a container matrix for drugs and electrolytes is particularly favored, in part due to the good biocompatibility of water compared with other liquid solvents such as ethanol and ethylene glycol. , so it is a better liquid solvent for electrotransporting drugs. Hydrogels have a high stable water content and can quickly absorb water. In addition, the hydrogel also has good biocompatibility with the skin and mucosal surface.

Of particular interest in transdermal drug delivery is the delivery of analgesic drugs for the management of moderate and severe pain. In order to avoid the potential danger of drug overdose and the pain caused by underdosing, the flow rate and timing of drug delivery are especially important for transdermal delivery of analgesic drugs.

One class of analgesic drugs that have been found for transdermal infusion are the synthetic anesthetics, a group of 4-aniline piperidines. Synthetic anesthetics such as fentanyl and certain derivatives thereof such as sufentanil are particularly suitable for transdermal delivery. These synthetic anesthetics are characterized by rapid action, high potency and short duration of action. Estimated to be 80 and 100 times more potent than morphine, respectively. These drugs are weakly basic, that is, amines, and the main components in acidic media are cations.

In a practical study to determine plasma concentrations, Thysman and Preat (Anesth. Analg. 77 (1993) pp. 6-66) compared the simple diffusion of fentanyl and sufentanil with that in citrate buffer solution at pH 5 electricity transmission. Simple diffusion does not produce any detectable plasma concentrations. Achievable plasma values depend on the maximum flux of the drug that can penetrate the skin and on the pharmacokinetic properties of the drug, such as gap and volume of distribution. Significantly reduced (1.5h vs. 14h) lag time (ie time required to reach peak serum values) of electrodelivery compared to passive transdermal patch delivery was reported. The researchers concluded that electro-delivery of these pain-relieving drugs could control pain more quickly than conventional patch delivery, and that the pulsed release of the drug (by controlling the electrical current) was comparable to conventional patch delivery. For example, see Thysman et al., Int.J.Pharma., 101 (1994) pp105-113; V. Preat et al., Int.J.Pharma., 96 (1993) pp.189-196 (sufentanil); Gourlav et al., Pain , 37 (1989) pp.193-202 (fentanyl); Sebel et al., Eur. J. Clin. Pharmacol. 32 (1987) pp. 529-531 (fentanyl and sufentanil). Passive, ie by diffusion, and electrically assisted transdermal delivery of narcotic analgesic drugs such as fentanyl for pain relief has also been disclosed in the patent literature. See, eg, US Patent 4,588,580 to Gale et al; US Patent 5,232,438 to Theeuwes et al.

In recent years, control of postoperative pain has looked to delivery systems other than electrical delivery. Of particular interest are devices and systems that enable a patient to control the amount of pain medication received, within predetermined limits. Experiments with these devices have shown that patient-controlled delivery of pain medication is smaller than physician-prescribed doses. Self-administration or patient-controlled self-administration has been referred to (as it is herein) as patient-controlled analgesics (PCA).

Known PCA devices are generally electromechanical pumps, which require a high capacity power source, such as an AC power supply or multiple large and bulky battery packs. Due to their bulk and complexity, commercially available PCA devices generally require the patient to be confined to a bed or some other substantially fixed position. Existing PCA devices deliver drugs to patients by inserting intravenous lines or catheters into veins, arteries or other organs by qualified medical personnel. This technique requires the skin to be punctured in order to deliver an analgesic (see US Patent 5,232,448 to Zdeb). Thus, when actually using the commercially available PCA devices, highly skilled medical personnel are required to initiate and monitor the operation of the PCA devices, with the attendant risk of infection. Furthermore, commercially available PCA devices are inherently somewhat painful to use due to their percutaneous (ie, intravenous or subcutaneous) entry.

This technology has somewhat hampered the development of transdermal electrotransport devices that could compete with traditional PCA in terms of delivered drug doses to achieve adequate analgesia and in a patient-controlled manner. In addition, little progress has been made to provide compositions of hydrogels for electrotransport of analgesics, especially for transdermal electrotransport of fentanyl, with long-term stability and electromechanical pumps that can be controlled by the patient. , for example for intravenous delivery of analgesics, compared performance properties. There is a need to provide an analgesic composition in a suitable device to take advantage of the convenience of electro-delivery in a small, self-contained, patient-controlled device.

The present invention provides a device for improved transdermal delivery of fentanyl and its analogs, especially sufentanil. The device of the present invention provides higher efficiency of electro-delivery of the analgesic fentanyl or sufentanil and provides greater safety and comfort to the patient in pain management. The above and other advantages of the present invention are provided by a device for delivering fentanyl or sufentanil through a human body surface (e.g., intact skin) by electrotransport, the device having at least a portion comprising a fentanyl/sufentanil salt. Anode donor container for aqueous solution.

The present invention provides a donor container composition for a transdermal electrotransport fentanyl/sufentanil delivery device having an anodic donor electrode made of silver that substantially blocks silver ions Migrates into the patient's skin and discolors the skin. While the prior art teaches that the use of halide salts of drugs has the advantage of preventing electrochemically generated migration of silver ions (see U.S. Patent 5,135,477 to Untereker et al.), it has now been found that the use of halide salts of pharmaceuticals has the advantage of preventing silver ion migration during longer periods of electrotransport (e.g., at least several hours) of halide salts of fentanyl or sufentanil for continuous or intermittent delivery, the amount of fentanyl/sufentanil halide in the donor container required to prevent migration of said silver ions must Substantially exceeds the amount of fentanyl/sufentanil halide required for therapeutic purposes. For fentanyl hydrochloride, the amount of drug required to prevent silver ion migration has been determined to be approximately at least under specific electrotransport conditions (i.e., applied electrotransport current, container size, weight, composition, and electrotransport current applied). The time) is at least three times the amount of drug that needs to be delivered to the patient, which will be described in detail later.

Other advantages, specific applications, structural modifications, and physical properties of the present invention will be more fully understood from the following detailed description, examples and appended claims when taken in conjunction with the accompanying drawings.

The present invention is described below in conjunction with accompanying drawing, wherein:

Figure 1 is a disassembled perspective view of an electrotransport drug delivery device according to the present invention.

The present invention generally relates to an improved device for the transdermal electrodelivery of fentanyl or sufentanil in the form of a water-soluble salt for systemic therapeutic effect. The present invention relates to a fentanyl or sufentanyl halide donor container composition suitable for use in an electrotransport device having a silver anodic donor electrode, the composition of which is useful for preventing a patient's skin from forming and forming during silver anodization. Discoloration caused by silver ions infused into the patient's skin along with drugs is effective.

Because fentanyl and sufentanil are alkaline, the salts of fentanyl and sufentanil are generally acid salts, such as citrate, nitrate, etc. The acid salts of fentanyl generally have a water solubility of about 25-30 mg/mL. The acid salts of sufentanil generally have a water solubility of about 45-50 mg/mL. When these salts are placed in solution (eg, an aqueous solution), the salt is decomposed and forms a protonated fentanyl or sufentanil cation and the opposite (eg, citrate or chloride) anion. The fentanyl/sufentanil cations are thus delivered from the anode of the electrodelivery device. Silver anodes have been proposed as electrodes for transdermal electrotransport devices in order to maintain the stability of the pH in the anode reservoir. See, eg, US Patent 5,135,477 to Untereker et al; US Patent 4,752,285 to Petelena et al. These patents also consider that one of the disadvantages of using silver anodes in electrotransport devices is that application of current through the silver anode oxidizes the silver ( ), thereby forming silver cations, which compete with cationic drugs for electrotransport into the skin. Silver ions migrating into the skin cause temporary epidermal discoloration (TED) of the skin. In addition to these patents, WO 95/27530 to Phipps et al. teaches the use of a supplemental source of chloride ions in the form of a high molecular weight chloride resin in the donor container of a transdermal electrotransport device. Although these resins are extremely effective at providing sufficient chloride to prevent silver ion migration and attendant skin discoloration when silver anodes are used for transdermal electrodelivery of fentanyl and sufentanil, these resins are also detrimental to the drug being delivered. (even if the drug sticks to the skin) and/or the patient's skin (ie, skin irritation). Thus, for the purposes of the following discussion, the donor vessel composition of the present invention will take the form of being substantially free of such secondary chloride ion source resins. Of course during operation of the transdermal electrotransport device, chloride ions from the patient's body will migrate from the skin into the anode reservoir. This inherent phenomenon also occurs during operation of the device of the present invention, and for example chloride flowing from the skin into the anode donor container is not considered a "supplementary source of halide/chloride ions" as the term is used herein. Although the patents of Untereker and Petelenz teach that providing cationic drugs in the form of halide salts can prevent the migration of silver ions (i.e., the formation of water-soluble silver halide precipitates by the reaction of silver ions and the halide counterions of drugs ), but it has now been established that a significant excess (i.e., substantially more than the amount of fentanyl halide salt required to be delivered to the patient for pain relief purposes) of fentanyl halide must be provided in a delivery device for the electrotransport of fentanyl , in order to prevent the migration of silver ions. This is especially true for electrotransport devices adapted to apply electrotransport currents for prolonged periods of time, for example greater than about 6 hours.

In general, the amount of "excess" fentanyl halide needed to prevent silver ion migration depends greatly on several factors, including the particular halide salt used (e.g., chloride, fluoride, bromine, etc. halide or iodide salt), the value of the applied electrotransport current, the size/weight/composition of the donor container, the applied electrotransport current density, and the length of time for which the electrotransport current is applied. We have determined that delivery of fentanyl hydrochloride from a polyvinyl alcohol-based donor container used to deliver fentanyl over a period of up to approximately 15 hours serves to prevent migration of silver ions during electrotransport. The amount of fentanyl HCl is approximately 2-3 times the amount of fentanyl HCl that would be delivered to the patient in the same time interval to produce and maintain analgesia.

In the particular case of an electrotransport device having a donor container based on polyvinyl alcohol containing fentanyl hydrochloride having a total weight (according to hydrate form) of about 0.3 g to 0.8 g, wherein the device (1) has and An anode donor electrode made of silver (e.g. silver foil or silver powder incorporated into a polymer film) in electrical contact with the donor vessel, (2) with a power supply supplying a DC current of approximately 190 μA-230 μA to the donor electrode and the counter electrode, (3) providing a current density of less than about 0.3 mA/ ^cm , which is equal to the total applied current divided by the skin contact area of the donor container, and (4) for up to about 80 individual doses of about 8-12 minute duration A current such that the fentanyl HCl loading required to induce and maintain analgesia is approximately 2.5-3.5 mg, and the fentanyl HCl loading required to prevent TED is at least approximately 8-10 mg, preferably at least about 11-13 mg. In particular, in electrotransport devices having a polyvinyl alcohol-based donor container containing fentanyl hydrochloride with a total weight of about 0.5-0.8 g (in terms of hydrate form), the device applies a direct current of about 210 μA to the electrodes, and With the ability to deliver this current for up to approximately 80 individual delivery intervals of approximately 10 minutes, the loading of fentanyl HCl required to induce and maintain analgesia was approximately 3 mg and the fentanyl HCl required to prevent TED The NiHCl loading is at least about 9 mg, preferably at least about 12 mg.

To determine the loading of halide salts other than fentanyl HCl, it is only necessary to present the vessel with an equimolar amount of halide ion, since silver halide salts have fairly consistently low water solubility. For example, a loading of 8-10 mg of fentanyl HCl corresponds to a molar loading of approximately 20-25 μmolar. Thus, any other fentanyl halide (eg, fentanyl fluoride, fentanyl bromide, fentanyl iodide) will provide an equal degree of silver migration inhibition as fentanyl HCl.

In addition to fentanyl, "excess" sufentanil halide salts can also be used to prevent silver ion migration. Because the potency of sufentanil is about 7-10 times that of fentanyl, the equivalent analgesic effect can be achieved as long as it is about 0.1-0.14 times the dose of fentanyl. However, because the delivery efficiency of sufentanil transdermal electrotransport (i.e. the amount of fentanyl delivered per unit of applied electrotransport current) is only about one-third that of fentanyl, the use of sufentanil for The applied electrotransport current required to achieve the same analgesic effect was approximately 0.3-0.4 times that required for fentanyl. Thus, the "excess" sufentanil chloride required to prevent silver ion migration during electrotransport of sufentanil is correspondingly reduced to about 6-10 μmol or about 2.4-4 mg. The loading of sufentanil HCl required to prevent silver ion migration was at least 4 times that required to achieve analgesic effect in the patient.

As long as the container matrix material has essentially no silver ion binding capacity (i.e., half through immobilized anions (e.g., COO ⁻ ), as found in cation exchange membranes), the particular matrix material selected for use as the donor container matrix is essential for effective silver ion binding. Minimal loading of halide salts of fentanyl and sufentanil added to patient skin to prevent cationic migration had no effect. Hydrogel matrices, in particular, exhibit little or no tendency to bind silver ions and are therefore the best matrix material for this aspect of the invention.

Preferably, the concentration of fentanyl or sufentanil in the solution in the donor container is maintained at or above a value at which the fentanyl/sufentanil flux and The drug concentration in the donor container is related during electrodelivery of the drug. Transdermal Electrotransported Fentanyl Flux Transdermal fentanyl flux begins to be related to the fentanyl concentration in the aqueous solution when the fentanyl concentration is below about 11-16 mM. This 11-16 mM concentration is calculated based only on the volume of liquid solvent used in the donor vessel, not the total volume of the vessel. In other words, the concentration of 11-16 mM does not include the volume of the container represented by the container matrix (eg, hydrogel or other matrix) material. Furthermore, the concentration of 11-16 mM is calculated based on the number of moles of fentanyl salt, not the number of moles of fentanyl radicals contained in the donor vessel solution. For fentanyl HCl, a concentration of 11-16 mM corresponds approximately to 4-6 mg/mL. Other fentanyl halide salts will vary slightly in weight depending on the concentration range based on the molecular weight of the counterion associated with the particular fentanyl salt. At concentrations of fentanyl salts around 11-16 mM, the flux of fentanyl transdermal electrotransport, even when the applied current was kept constant, began to decrease significantly. Therefore, to ensure a predictable flux of fentanyl at a particular applied current, the concentration of the fentanyl salt in the solution contained in the donor container is preferably maintained above about 11 mM, more preferably above about 16 mM. In addition to fentanyl, water-soluble sufentanil salts also have a minimum aqueous solution concentration below which the flux of transdermal electrotransport is related to the concentration of sufentanil in solution. The minimum concentration for sufentanil is approximately 1.7 mM.

The present invention provides an electrotransport device for delivering fentanyl or sufentanil through a human body surface such as skin to achieve analgesic effect. The fentanyl or sufentanil salt is preferably provided in the donor container of the electrotransport device as a clear saline solution.

For patients weighing about 35 kg or more, the dose of fentanyl delivered transdermally is about 20 μg to about 60 ug over a delivery time of up to about 20 minutes. Preferably, the dose of fentanyl delivered is about 35-45 [mu]g, more preferably the dose of fentanyl delivered is about 40 [mu]g in the delivery interval. The device of the present invention also preferably includes means for delivering about 10 to 100 additional, preferably about 20 to 80 additional identical doses within a 24 hour period to achieve and maintain analgesic effect.

For patients weighing about 35 kg or more, the dose of sufentanil delivered transdermally ranges from about 2.3 μg to about 7.0 μg over a delivery time of up to about 20 minutes. Preferably the dose of sufentanil delivered is about 4-5.5 [mu]g, more preferably the dose of sufentanil delivered during delivery is about 4.7 [mu]g. The device of the present invention preferably also includes means for delivering about 10 to 100 additional, preferably about 20 to 80 additional doses of sufentanil over a 24 hour period to achieve and maintain analgesic effect.

The composition of the anodic reservoir containing fentanyl/sufentanil salt for transdermal delivery of the above doses of fentanyl/sufentanil by electrotransport preferably includes soluble fentanyl/sufentanil Clear aqueous solutions of salts such as HCl or citrate. Preferably, the clear solution is contained within a hydrophilic polymer matrix such as a hydrogel matrix. The fentanyl/sufentanil salts should be present in sufficient quantities to deliver the aforementioned doses transdermally at delivery intervals of up to about 20 minutes in order to achieve systemic analgesia. The fentanyl/sufentanil salt generally comprises about 1 to 10 wt% of the donor vessel composition (including the weight of the polymer matrix) based on the entire hydrate, more preferably comprises about 1 to 5 wt% of the entire hydrate donor vessel composition %. While not critical to this aspect of the invention, it is noted that applied current densities are generally in the range of about 50-100 μA/cm ² and applied electrotransport currents are generally in the range of about 150-240 μA.

Hydrogels containing anodic fentanyl/sufentanil salts can be composed of many materials, but are preferably composed of hydrophilic polymeric materials, preferably neutral in polarity, to increase drug stability . Suitable polar polymers for the hydrogel matrix include a variety of synthetic and naturally occurring polymeric materials. A preferred hydrogel composition contains a suitable hydrophilic polymer, buffer, humectant, thickener, water and a water-soluble fentanyl or sufentanil salt (eg, HCl salt). A preferred hydrophilic polymer matrix is polyvinyl alcohol, such as water-soaked and fully hydrolyzed polyvinyl alcohol (PVOH), such as Mowiol 66-100 commercially available from Hoechst AG. Suitable buffers are ion exchange resins, which are copolymers of methacrylic acid and vinylbenzene in acid and salt form. Another example of such a buffer is a mixture of Polacrilin (copolymer of methacrylic acid and divinylbenzene available from Rohm & Haas, Philadelphia, PA) and its potassium salt. A mixture of acid and the potassium salt form of Polacrilin was used as a copolymer buffer to adjust the pH of the hydrogel to about pH 6. The use of humectants in the hydrogel composition is advantageous in preventing moisture loss from the hydrogel. An example of a suitable humectant is guar gum. Thickeners are also advantageous in the composition of the hydrogel. For example, polyvinyl alcohol thickeners such as hydroxypropyl methylcellulose (e.g., Methocel K 100MP available from Dow Chemical, Midland, MI) help improve the rheology of hot polymer solutions placed into a mold or cavity characteristic. Hydroxypropyl methylcellulose increases viscosity on cooling, greatly reducing the tendency of the cooled polymer solution to overflow the mold or cavity.

In a preferred embodiment, the anode fentanyl/sufentanil hydrogel composition comprises about 10-15 wt% polyvinyl alcohol, 0.1-0.4 wt% resin buffer, and about 1-2 wt% Fentanyl or sufentanil salt, preferably hydrochloride. The rest is water and ingredients such as humectants, thickeners, etc. Polyvinyl alcohol (PVOH) based hydrogel compositions were prepared by mixing all materials including fentanyl or sufentanil salts in a vessel at a temperature of about 90-95°C for at least about 0.5 hours. The hot mixture is then poured into a foam mold and stored overnight at a freezer temperature of approximately -35°C to allow for cross-linking with the PVOH. When warmed to room temperature, a strong elastic gel for fentanyl electrotransport was obtained.

The composition of the hydrogel was used in the electrotransport device described below. Suitable electrotransport means include an anodic donor electrode, preferably composed of silver, and a cathodic counter electrode, preferably comprising silver chloride. The donor electrode is in electrical contact with a donor container containing a clear solution of fentanyl/sufentanil salts. As noted above, the donor container is preferably composed of a hydrogel. Conversely the container also preferably comprises a biocompatible electrolyte solution (eg clear) comprising eg citrate buffered saline. The anode and cathode hydrogel containers each preferably have a skin contact area of about 1-5 cm ² , more preferably about 2-3 cm ² . The anode and cathode hydrogel containers preferably have a thickness of about 0.05-0.25 cm, more preferably about 0.15 cm. The applied electrotransport current is approximately 150 μA-240 μA depending on the desired analgesic effect. Preferably, the electrotransport current applied during dosing is a substantially constant direct current.

Referring now to Figure 1, there is illustrated an example of an electrotransport device that may be used in accordance with the present invention. Figure 1 shows an exploded perspective view of an electrotransport device 10, with an activation switch 12 in the form of a button, and a display device 14 in the form of a light emitting diode (LED). Device 10 includes upper housing 16 , circuit board assembly 18 , lower housing 20 , anode 22 , cathode 24 , anode receptacle 26 , cathode receptacle 28 and skin-compatible connector 30 . The upper housing 16 has lateral wings 15 to aid in securing to the skin. Upper housing 16 is preferably formed from an injection moldable elastomer (eg, vinyl). The printed circuit board assembly 18 includes an integrated circuit board 32 connected to discrete circuit components 40 and a battery 32 . The circuit board assembly 18 is connected to the housing 16 by posts (not shown in FIG. 3 ) passing through openings 13 a and 13 b , the ends of which are heated/melted to thermally couple the circuit board assembly 18 to the housing 16 . The lower shell 20 is connected to the upper shell 16 through a connector 30, and the upper surface 34 of the connector 30 is connected to the lower shell 20 and the upper shell 16 including the bottom surface of the transverse wing 15.

On the underside of the circuit board assembly 18 is shown (partially) a battery 32 which is preferably a button cell such as a lithium cell. Other types of batteries may be used to power device 10 .

The circuit outputs (not shown in FIG. 1 ) of the circuit board assembly 18 are contacted to the electrodes 24, 22 through openings 23, 23' in recesses 25, 25' formed in the lower housing by means of conductive tabs 42, 42'. The electrodes 22 , 24 are in turn electromechanically connected directly to the top sides 44 , 44 ′ of the drug containers 26 , 28 . The bottom sides 46', 46 of the drug containers 26, 28 contact the patient's skin through the openings 29', 29 of the connector 30. Upon depression of pushbutton switch 12, electronic circuitry on circuit board assembly 18 provides a predetermined DC current to electrodes/reservoirs 22, 26 and 24, 28 for a predetermined length of delivery interval, eg, about 10 minutes. Preferably the device provides a visual or audible signal to the user that delivery of the drug or preconditioning agent is initiated, either by illuminating LED 14 or by emitting an audible signal from a buzzer. Pain relief medication such as fentanyl is then delivered through the skin, eg, on the patient's arm, at predetermined time intervals (eg, 10 minutes). In fact, the user knows the start of the drug delivery interval by seeing (the LED 14 lights up) and hearing (the buzzer sounds) the signal.

The anode 22 is preferably made of silver and the cathode is preferably made of silver chloride. Containers 26, 28 are preferably made of a polymeric hydrogel material. The electrodes 22 , 24 and containers 26 , 28 are held by the lower housing 20 . For fentanyl and sufentanil salts, the anode reservoir 26 is the "donor" reservoir, which contains the drug, and the cathode reservoir 28 contains the biocompatible electrolyte.

The pushbutton switch 12 , the electronic circuitry on the circuit board assembly 18 and the battery 32 are "sealed" disposed between the upper housing 16 and the lower housing 20 . Upper housing 16 is preferably made of rubber or other resilient material. The lower housing 20 is preferably made of a plastic or elastomeric material such as polyethylene so that the recesses 25, 25' can be easily molded and the openings 23, 23' formed by cutting. The assembled device 10 may be water-resistant (ie, splash-proof), preferably waterproof. The system has a flat shape, making it easy to move around the setting. The anode/drug reservoir 26 and cathode/salt reservoir 28 are located on the skin-contacting side of the device 10 with sufficient distance to prevent electrical shorting during normal operation.

Device 10 is secured to a patient's body surface (eg, skin) by means of peripheral attachment means 30 having an upper side 34 and a body contacting side 36 . The attachment side 36 has an adhesive function ensuring it is held in place during normal use and can be removed after a predetermined wearing period (eg 24 hours). The upper adhesive side 34 joins the lower housing 20 and holds the electrodes and drug container in the housing recesses 25, 25' and keeps the lower housing 20 attached to the upper housing 16.

A push button switch 12 is located on the top side of the device 10 and is easily actuated by clothing. It is preferable to activate the device 10 to deliver the drug by pressing the button switch 12 twice within a short period of time, eg, within 3 seconds, so as to reduce misuse of the device 10 .

When the switch is activated, an audible warning signal announces the initiation of drug delivery, at which point the circuit applies a DC current of a predetermined value to the electrode/reservoir for a predetermined delivery interval (eg, 10 minutes). Throughout the delivery period, LED 14 remains "ON", indicating that device 10 is in the drug delivery mode. The battery should have sufficient capacity to power the device 10 at a predetermined DC current for an entire wearing period (eg, 24 hours).

The present invention is further explained by the following examples, which are for illustration only and do not limit the scope of the present invention.

example 1

The following study was performed to determine the amount of fentanyl hydrochloride drug loading required to prevent temporary discoloration of the outer skin by preventing silver migration in a transdermal drug electrodelivery device having a skin weight of approximately 0.6 g With a donor vessel gel contact area of approximately 2.8 ^cm2 , the device was worn for up to 24 hours with an electrotransport current of 240 μA (i.e., a current density of 87 μA/ ^cm2 ) applied at approximately 10-minute delivery intervals , in order to deliver a dose of 40 μg, and up to 80 such doses can be delivered during a 24-hour wearing period. Thus, the device has the capacity to deliver up to 3.2 mg of fentanyl (80 x 40 μg = 3.2 mg) for therapeutic purposes.

A donor container with a total weight of approximately 0.15 g based on polyvinyl alcohol-containing fentanyl HCl (PVOH) hydrogel consisted of the following components:

Material (wt%)

Water 80.8

PVOH 15.0

Fentanyl HCl 2.0

Polacrilin 0.1

0.5N NaOH 2.1

The materials were mixed in a hooded beaker at 90°C, then 0.15g aliquots of the liquid gel were placed into foam molds and frozen at -15°C to -50°C overnight. The gel becomes a disk with an area of 1.0 cm2 ^and a thickness of 1.6 mm.

Silver foil was laminated on the surface of each gel to form an anode donor electrode assembly comprising a silver foil anode and a fentanyl-containing gel container. The opposite electrode assembly containing citrate buffered saline (pH 4) was made using PVOH gel of the same size. A silver chloride cathode electrode (ie a polyisobutylene film to which silver chloride powder is added) is laminated on one surface of the opposing gel. The electrodes were electrically connected to a conventional power supply providing a constant DC current of 240 μA (877 μA/cm ² ).

The electrotransport system was worn on the upper outer arms of 6 male volunteers for 15 hours, which was approximately 10% longer than the maximum time the current was applied by the system (i.e. 80 x 10 minutes = 13.3 hours), during the 15 hours of wear During the test period, the system continuously applied current, after which the system was removed and each subject's arm was rigorously examined to determine whether a transient skin discoloration (TED) caused by migration of silver ions formed in the anode assembly occurred. Subjects were checked again 1 hour and 24 hours after the system was removed to confirm the initial TED reading. In all 6 subjects, no TED occurred at the site where the anode assembly was attached. This suggests that loading of about 1.8 to 2 wt% or about 3 mg of fentanyl HCl in these gels provided sufficient chloride ions for preventing migration of silver ions formed by oxidation of the silver anode during 15 hours of wear into patient skin. Thus, during the maximum dose period of 13.3 hours, even under the condition of maximum dose, the electrotransport system applied the same value of electrotransport current also did not exhibit TED. The 2 wt% fentanyl HCl loading in these PVOH-based donor gel containers can be scaled up to larger containers. Thus, for a PVOH-based fentanyl-HCl-containing donor container having a total weight of approximately 0.6 g that is substantially free of other sources of chloride ions other than drug counter ions, the fentanyl-HCl loading should be at least Approximately 11 mg (ie 1.8 wt% x 0.6 g = 11 mg), although the maximum amount of fentanyl that can be delivered to a patient from the device during a 24 hour wearing period is only approximately 3.2 mg of fentanyl. Thus, under conditions of maximum dosage, in order to prevent the migration of silver ions in the device, an excess of fentanyl HCl must be loaded into the anode donor container, this excess loading is about the amount of fentanyl required for therapeutic purposes. 3-4 times the amount of thanis.

In summary, the present invention provides a device for improved transdermal electrotransport of water-soluble salts of fentanyl and sufentanil. Such an electrotransport device has a silver anode donor electrode preferably with a hydrogel based donor vessel. The electrotransport device is preferably a patient controlled device. The composition of the hydrogel contains a drug concentration sufficient to prevent migration of silver ions into the skin of the wearer of the electrotransport device and thus prevent temporary epidermal discoloration, and provide acceptable analgesia.

Claims (22)

1. An electrotransport device (10) for transdermal delivery of only a total amount of an analgesic drug selected from the group consisting of fentanyl halide salts and sufentanil halide salts, the device comprising a silver anodic donor electrode (22) and a cathodic counter electrode (24), and means for limiting the amount of analgesic drug delivered to said total amount, the donor electrode (22) being in electrical contact with a donor reservoir (26) containing the analgesic drug, the donor reservoir (26) being free of a source of halide other than the analgesic drug halide, the device characterized by:

the donor container (26) contains a loading amount of the halide salt of the selected analgesic drug that is at least 2 times greater than the amount required to achieve the analgesic effect.

2. The device of claim 1, wherein the analgesic drug is fentanyl HCl or sufentanil HCl.

3. The device of claim 1, wherein the analgesic drug comprises fentanyl halide.

4. The device of claim 1, wherein the analgesic drug comprises sufentanil halide, said loading being in an amount at least 4 times greater than said total amount delivered transdermally.

5. The device of claim 1, wherein the device includes a current source (32) that applies an electrotransport current to the donor and counter electrodes (22, 24).

6. The device of claim 1, wherein the device is adapted to deliver the analgesic drug over a delivery period of at least 6 hours.

7. The device of claim 6, wherein the delivery period is a cumulative time interval comprising a plurality of analgesic drug delivery intervals.

8. The device of claim 1, wherein the donor reservoir (26) has a weight of 0.5g to 0.8g based on hydrate, the delivery device has a current source (32) for supplying a direct current of 190 μ Α to 230 μ Α to the donor and counter electrodes (22, 24) for up to about 100 individual delivery intervals, each delivery interval having a duration of 8 to 12 minutes, and the donor reservoir (26) contains at least 9mg of fentanyl hydrochloride.

9. The device of claim 8, wherein the donor reservoir (26) contains at least 12mg of fentanyl hydrochloride.

10. A method for transdermal delivery of a total amount of an analgesic drug to a device (10), comprising the steps of:

selecting a drug from the group consisting of fentanyl halide salts and sufentanil halide salts;

providing a donor container (26) containing an analgesic drug;

providing a silver anode donor electrode (22) in electrical contact with the donor reservoir (26), and a cathode counter electrode (24);

providing means for limiting the amount of analgesic drug delivered to said total amount; and

a current source (32) for applying an electrotransport current to the donor and counter electrodes (22, 24),

wherein the donor container (26) is free of a halide source other than the analgesic halide,

the method is characterized by placing a loading amount of the halide salt of the analgesic drug in the donor container (26), said loading amount being at least 2 times greater than the amount required to achieve the analgesic effect.

11. The method of claim 10, wherein the analgesic drug is fentanyl HCl or sufentanil HCl.

12. The method of claim 10, wherein the analgesic drug comprises fentanyl halide.

13. The method of claim 10, wherein the analgesic drug comprises sufentanil halide and the loading is in an amount at least 4 times greater than the total amount delivered transdermally.

14. The method of claim 10, wherein the device (10) delivers the analgesic drug over a delivery period of at least 6 hours.

15. The method of claim 14, wherein the delivery period is a cumulative time interval comprising a plurality of analgesic drug delivery intervals.

16. The method of claim 10, wherein the donor reservoir (26) has a weight of 0.5g to 0.8g based on hydrate, and loading at least 9mg of fentanyl hydrochloride into the donor reservoir (26) provides 190 μ Α to 230 μ Α of direct current to the donor and counter electrodes (22, 24), the direct current being provided by a current source (32), the phase flow currents being provided over up to about 100 individual delivery intervals, each delivery interval having a duration of 8 to 12 minutes.

17. The method of claim 15, comprising loading the donor reservoir (26) with at least 12mg of fentanyl hydrochloride.

18. An anodic fentanyl formulation for an electrotransport device (10) for transdermal delivery of a total amount of fentanyl halide salt, the electrotransport device (10) comprising a silver anodic donor electrode (22) in contact with said composition, a cathodic counter electrode (24), means for limiting the amount of said analgesic drug delivered to said total amount, and a power source (32) connected to the donor and counter electrodes (22, 24), said formulation comprising a hydrophilic matrix comprising a transparent solution of fentanyl halide salt, said formulation characterized by:

the amount of fentanyl halide loaded was: (i) at least 2 times greater than said total amount, and (ii) sufficient to prevent temporary epidermal skin discoloration during and after transdermal electrotransport of fentanyl.

19. The formulation of claim 18 wherein the fentanyl halide salt comprises from about 1.7% to about 2.0% by weight of the composition.

20. The formulation of claim 18 wherein the fentanyl halide salt comprises from about 1.9% to about 2.0% by weight of the composition.

21. The formulation of claim 18 wherein the fentanyl halide is fentanyl hydrochloride.

22. The formulation of claim 18, wherein the hydrophilic matrix comprises polyvinyl alcohol.

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